Inflammatory bowel diseases (IBD) are prevalent in Western countries. In North America and Europe, over 1.5 million and 2 million people suffer from the disease, respectively.1 In newly industrialized countries (NICs), IBD incidence and prevalence is lower; however, recent studies describe increasing rates including Latin America (LATAM).2,3 Main reasons for this epidemiological trend may include socioeconomic (environmental changes, urbanization, lifestyle modifications) as well as health-care related factors (increased IBD awareness).2

Anti-tumor necrosis factor (anti-TNF) agents were introduced during early 2000s for IBD treatment.4 These molecules have been shown to be effective both in inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis (UC) and Crohn's disease (CD). Nevertheless, up to 22% of UC patients and 31% of CD patients are considered primary non-responders (PNR) to anti-TNF induction therapy. Furthermore, it has been estimated that 49%–59% of UC and 23%–64% of CD patients lose response to anti-TNF agents over time (secondary loss of response [SLOR]).5,6 As a consequence, UC and CD patients receiving anti-TNF agents may require dose optimization (escalation of dose and/or frequency of administration), treatment discontinuation or initiation of another biologic agent (switching or class swapping), augmentation of concurrent non-biologic therapy, or surgery. All these strategies are considered as indicators of suboptimal response to anti-TNF therapy.7,8

Since the epidemiology and clinical patterns of IBD differ between different countries and communities, the response to drugs could also be different due to several reasons, including microbiota, genetics and different treatment patterns.9,10 Data on anti-TNF treatment patterns and suboptimal response among IBD patients in LATAM are scarce. The EXPLORE study aimed to describe the incidence and indicators of suboptimal response to anti-TNF therapy in UC and CD patients in the clinical setting in NICs, including Asia-Pacific, LATAM, Russia and the Middle East regions.11 This study showed that suboptimal response to anti-TNF agents is common in IBD patients residing in NICs, but differences were reported across the regions.

We conducted a sub-analysis of the EXPLORE study in LATAM countries, with a focus on real-world suboptimal response of IBD patients to a first anti-TNF agent, diagnosis journey, barriers to anti-TNF prescription, local treatment pathways and other aspects specific to the region, such as the prevalence of opportunistic infections, especially TB.

The present study describes the largest cohort of LATAM IBD patients with anti-TNFs utilization to date. Our main goal was to establish the CISR to anti-TNF agents in UC and CD patients in LATAM participants of the EXPLORE study.11 Our results showed that suboptimal response to the first anti-TNF for both conditions is common in LATAM, occurring in more than one-third of UC patients (36.4%) and nearly half of CD patients (46.5%) at 24 months, respectively. A multinational retrospective chart review study from Europe and Canada (n=1195 subjects) showed that more than half of IBD patients (CU: 64.1%; CD: 58.1%) had at least one indicator of suboptimal response to anti-TNFs at 24 months.12 In the latter study, infliximab users represented 92.2% and 55.6% of UC and CD patient cohorts, respectively. A nationwide population study in South Korea showed a higher CISR in UC patients at 24 months (80.5%).13 Similarly, a large commercial U.S. claims database study found that 86% of both, UC and CD patients experience at least one indicator of suboptimal response at 24 months.14 In the present study, PNR CI rate was 11.4% for UC and 10.8% for CD patients. Both percentages were slightly lower compared with the main study (13.6% and 16.9%, respectively). In contrast, SLOR rates in LATAM for both diseases were higher compared to the main EXPLORE study.11

Shin et al. found that UC patients receiving adalimumab were significantly more likely to experience at least one suboptimal response than those patients on infliximab (representing 56.2% of the overall UC patient population), driven by a higher risk of drug discontinuation and dose escalation.13 Thus, variations in the proportion of the different anti-TNF agents are expected to impact the rate of suboptimal response to these therapies. In the present study, the most frequent first-line anti-TNF agent for UC patients was infliximab, while adalimumab was the most prescribed agent for CD subjects. Nearly 45% of adalimumab prescriptions were related to the preferred route of administration. Of note, adalimumab was frequently prescribed for both UC and CD in Argentina. Several country-specific differences were reported in prescription rates, availability, accessibility, and local experience may partly explain such differences. Overall, most patients received anti-TNFs at infusion centers; however, self-administration or home infusion was common in Argentina and Mexico, but infrequent in Colombia.

Differences in the incidence of suboptimal response to anti-TNFs, and the most frequent suboptimal indicator were observed across countries and indications, probably reflecting different IBD management practices. The most common indicator of suboptimal response among LATAM patients was augmentation of non-biologic therapies (UC: 41.7%; CD: 35%), while IBD-related hospitalization was the leading indicator in the main study (UC: 33%; CD: 36.1%), driven by Asia-Pacific and Russia/Middle East cohorts.11 In fact, IBD-related hospitalizations were the main indicator of suboptimal response in the Chinese cohort of the EXPLORE study, where patients presented with a more complicated disease at index (early disease onset, perianal involvement).15 Nevertheless, augmentation with non-biologic therapies was the second indicator of suboptimal response in the main EXPLORE study and in the Chinese cohort.11,15 Shin et al. also identified augmentation of conventional therapy as the most frequent indicator of suboptimal response in UC (47.6%) in South Korea, while Lindsay et al. showed anti-TNFs discontinuation (UC: 34.2%; CD: 31.1%) and dose escalation (UC: 29.7%; CD: 21.3%) as leading indicators in Europe and Canada, probably reflecting better access to advanced therapy in the latter study.12,13 It should be noted that IBD-related surgery rate (20%) was also an important indicator of suboptimal response among CD LATAM patients. Augmentation of concomitant non-biological therapies is more feasible than increasing anti-TNF doses or switching biologics due to several barriers. The lack of therapeutic drug monitoring strategies in LATAM to determine anti-drug antibodies and trough drug levels in real clinical practice might have played a role in these findings. The presence of anti-drug antibodies and circumstances that favor immunogenicity, such as lack of regular drug supply, which is frequent in our region, may be related to loss of response. The latter may lead to consideration of both augmentation with non-biologic therapies and anti-TNF drug dose escalation as frequent strategies.2

We found a noticeably lower incidence of suboptimal response in Mexico that can be related to a lower-than-expected frequency of non-biologic therapy prior to anti-TNF therapy initiation. A possible explanation may be a suspected gap in documentation, which might have led to an underestimation of the incidence of suboptimal response in the current analysis. This is supported by the higher CISR observed in patients with a documented history of non-biological therapy within two years prior to anti-TNF initiation versus those with no history of non-biologic use within 2 years prior to anti-TNF initiation.8,11

New publications highlighted the complexity of implementing updated international guidelines in LATAM countries due to limitations in treatment availability, access, reimbursement, and the presence of endemic diseases contraindicating the use of some drugs.3,11,16 The proportions of UC and CD LATAM patients who were medically indicated for anti-TNF therapy and did not receive such treatments were lower than reported in the overall EXPLORE cohort. LATAM patients who were treated with anti-TNF agents had more severe and prolonged disease; these characteristics may explain such difference, and possibly, a lower response rate to these drugs could be inferred. Local practice preferences and drug accessibility should also be taken into consideration as other potential causes of differences.

Data on TB reported in this study showed that TB remains endemic in LATAM and our detection rates are consistent with local literature.17,18 Of note, wide variations were reported among LATAM countries, even though our small sample, as aforementioned. In accordance with our data, Fortes et al. found a positive rate of 10.9% in a series of 184 Brazilian patients with IBD screened for LTB before starting immunosuppressive or immunobiological therapy.19 Despite recommended LTB screening, patients treated with anti-TNFs in endemic areas remain at risk of TB infections. According to a meta-analysis including more than 130,000 patients from several regions worldwide, there is a definite risk of TB related to anti-TNFs use in patients with IBD, primarily depending on the local TB burden and being independent of disease or treatment type.20 Thus, given the high incidence of active TB in LATAM countries and the concern of reactivation of LTB with anti-TNF therapies, the need for safer treatment strategies with lower risk of reactivation is recognized.19,21 Anti-TNF may only be preferred for specific patient subgroups in LATAM.22 Updated American and European guidelines endorse the indication of newer drugs to be used also as first-line treatments.23–25 Furthermore, vedolizumab and ustekinumab may be chosen over anti-TNF in elderly patients, patients with a history of neoplasia, and TB endemic areas.21,26

Despite the considerable incidence of suboptimal response to anti-TNFs, we found a low rate of anti-TNF therapy discontinuation (UC: 13.9%; CD: 10.0%) that could partly be due to the lack of other advanced therapies available during the study period. The therapeutic management of IBD patients experiencing loss of response to anti-TNF therapy has become a critical issue. The emergence of several promising agents (biologics and small molecules) suggests they may replace or be used in combination with anti-TNF agents in the near future, which in the latter case will likely improve treatment persistence with anti-TNFs. According to recent data, anti-TNF drugs continue to be the biological therapies with the highest prescription rates in LATAM.27,28

In LATAM, there is little information about physicians’ decisions to prescribe anti-TNF agents to IBD patients. We found that patient affordability and late referral to IBD specialist care centers (27% for both variables) were the most commonly reported barriers, while late diagnosis (40%) was perceived as the main barrier to prescription for non-IBD GI specialists. These results highlight the delay in CD diagnosis for a significant proportion of LATAM patients that has also been reported in a recent multicenter study including 9 LATAM countries.28

Limitations of the present study include its retrospective design and possible incomplete information in the medical records, as evidenced by the lower suboptimal response rate compared to other studies which used similar clinical parameters for anti-TNF loss of response.12–14 Also, the present study did not evaluate predictors of suboptimal response in this patient cohort. However, it should be emphasized that the present study describes useful insights into the IBD LATAM population, usually underrepresented in clinical trials of anti-TNF agents.

We observed that suboptimal response to anti-TNF therapy was common among IBD patients in LATAM, where augmentation with non-biologic therapy represented the most frequent indicator of suboptimal response. Overall, our findings contribute to the current body of evidence on the unmet needs associated with anti-TNF agents, especially in the era of newer IBD therapies with novel mechanisms of action, where a personalized approach may improve long-term outcomes in IBD patients in LATAM.

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

All authors participated in the acquisition, analysis, and interpretation of the data, drafted the initial manuscript and revised the article critically for relevant intellectual content.

This retrospective analysis was sponsored by Takeda Argentina S.A.

Balderramo, DC has received travel support from Takeda, Abbvie, Janssen and Ferring, received lecture fees from Takeda, Abbvie and Janssen, and participated at advisory boards from Takeda. Yamamoto-Furusho, JK is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd; has received honoraria from AbbVie, Takeda, Janssen, Farmasa, Ferring, Alfasigma, Hospira, UCB, Danone, Almirall and Pfizer as a speaker, key opinion leader, and member of national and international advisory boards; has received research funds from Bristol, Shire, Pfizer and Takeda and former President of the Pan American Crohn's and Colitis Organization (PANCCO). Ponce de Leon, E is a consultant or advisory/board member for AbbVie, Janssen and Takeda Pharmaceuticals Company Ltd. De Maria, J has received travel support from Takeda, Abbvie and Janssen. Zubiaurre, has received travel support from Takeda and Abbvie, received lecture fees from Takeda, Abbvie, Janssen and Ferring, participated at advisory boards from Takeda and Abbvie, and is a consultant for Takeda and Abbvie. Pedreira, SC has nothing to declare. Brion, L; Lis, C are Takeda Argentina employees. De Paula, JA has received travel support from Takeda, Abbvie, Janssen and Ferring, received lecture fees from Takeda, Abbvie, Janssen, Ferring and Shire (now part of Takeda), received financial support for research from Danone, participated at advisory boards from Takeda, Abbvie and Janssen and held preceptorship programs funded by Takeda, Abbvie and Janssen.